Apoptotic nanovesicle-reinforced GelMA hydrogel promotes inflammatory skin wound healing

Objectives Inflammation-dominant skin wounds are difficult to repair because persistent immune dysregulation disrupts the coordinated progression of wound healing. Although apoptotic vesicles have shown potential for immunomodulation and tissue regeneration, their application is limited by low yield, heterogeneity, and insufficient local retention. This study aimed to develop engineered apoptotic nanovesicles with enhanced pro-repair activity and improve their local delivery using a gelatin methacryloyl (GelMA) hydrogel. Methods Human umbilical vein endothelial cells (HUVECs) were subjected to UVB-induced apoptosis followed by gradient extrusion to generate apoptotic HUVEC-derived nanovesicles (AHNVs). Their pro-repair and immunomodulatory effects were compared with nanovesicles derived from non-apoptotic HUVECs. AHNVs were subsequently incorporated into GelMA hydrogel, and the resulting AHNVs@Gel system was evaluated for biocompatibility, release behavior, wound-site retention, and therapeutic efficacy in a murine inflammatory full-thickness skin wound model. Transcriptomic analysis was also performed in LPS-stimulated bone marrow-derived macrophages. Results Compared with non-apoptotic nanovesicles, AHNVs more effectively promoted endothelial migration and angiogenic activity and facilitated macrophage phenotypic transition in vitro. AHNVs@Gel showed favorable biocompatibility, sustained vesicle release, and improved early wound-site retention. In vivo, AHNVs@Gel accelerated wound closure and was associated with enhanced re-epithelialization, collagen deposition, angiogenesis, and inflammatory resolution. Transcriptomic analysis further indicated attenuation of interferon-associated inflammatory programs following AHNV treatment. Conclusions Engineering apoptotic nanovesicles by gradient extrusion and combining them with hydrogel-based local delivery provides a feasible strategy to enhance regenerative and immunomodulatory effects in inflammation-dominant skin wounds.